scholarly journals Negative Transpulmonary Pressure Disrupts Airway Morphogenesis by Suppressing Fgf10

2021 ◽  
Vol 9 ◽  
Author(s):  
Alice E. Stanton ◽  
Katharine Goodwin ◽  
Aswin Sundarakrishnan ◽  
Jacob M. Jaslove ◽  
Jason P. Gleghorn ◽  
...  
Keyword(s):  
Critical Role ◽  
Transpulmonary Pressure ◽  
Branching Morphogenesis ◽  
Surgical Approaches ◽  
Congenital Defects ◽  
Mechanical Signaling ◽  
Culture Model ◽  
Fibroblast Growth Factor 10 ◽  
Pseudoglandular Stage ◽  
Number Of Branches

Mechanical forces are increasingly recognized as important determinants of cell and tissue phenotype and also appear to play a critical role in organ development. During the fetal stages of lung morphogenesis, the pressure of the fluid within the lumen of the airways is higher than that within the chest cavity, resulting in a positive transpulmonary pressure. Several congenital defects decrease or reverse transpulmonary pressure across the developing airways and are associated with a reduced number of branches and a correspondingly underdeveloped lung that is insufficient for gas exchange after birth. The small size of the early pseudoglandular stage lung and its relative inaccessibility in utero have precluded experimental investigation of the effects of transpulmonary pressure on early branching morphogenesis. Here, we present a simple culture model to explore the effects of negative transpulmonary pressure on development of the embryonic airways. We found that negative transpulmonary pressure decreases branching, and that it does so in part by altering the expression of fibroblast growth factor 10 (Fgf10). The morphogenesis of lungs maintained under negative transpulmonary pressure can be rescued by supplementing the culture medium with exogenous FGF10. These data suggest that Fgf10 expression is regulated by mechanical stress in the developing airways. Understanding the mechanical signaling pathways that connect transpulmonary pressure to FGF10 can lead to the establishment of novel non-surgical approaches for ameliorating congenital lung defects.

scholarly journals In vitro models of fetal lung development to enhance research into congenital lung diseases

2021 ◽  
Author(s):  
Soichi Shibuya ◽  
Jessica Allen-Hyttinen ◽  
Paolo De Coppi ◽  
Federica Michielin
Keyword(s):  
Lung Development ◽  
Lung Diseases ◽  
Ex Vivo ◽  
Fetal Lung ◽  
Branching Morphogenesis ◽  
In Vitro Models ◽  
Normal Lung ◽  
Novel Therapeutic Strategies ◽  
Pseudoglandular Stage

Abstract Purpose This paper aims to build upon previous work to definitively establish in vitro models of murine pseudoglandular stage lung development. These can be easily translated to human fetal lung samples to allow the investigation of lung development in physiologic and pathologic conditions. Methods Lungs were harvested from mouse embryos at E12.5 and cultured in three different settings, i.e., whole lung culture, mesenchyme-free epithelium culture, and organoid culture. For the whole lung culture, extracted lungs were embedded in Matrigel and incubated on permeable filters. Separately, distal epithelial tips were isolated by firstly removing mesothelial and mesenchymal cells, and then severing the tips from the airway tubes. These were then cultured either in branch-promoting or self-renewing conditions. Results Cultured whole lungs underwent branching morphogenesis similarly to native lungs. Real-time qPCR analysis demonstrated expression of key genes essential for lung bud formation. The culture condition for epithelial tips was optimized by testing different concentrations of FGF10 and CHIR99021 and evaluating branching formation. The epithelial rudiments in self-renewing conditions formed spherical 3D structures with homogeneous Sox9 expression. Conclusion We report efficient protocols for ex vivo culture systems of pseudoglandular stage mouse embryonic lungs. These models can be applied to human samples and could be useful to paediatric surgeons to investigate normal lung development, understand the pathogenesis of congenital lung diseases, and explore novel therapeutic strategies.

PDGF-AA and its receptor influence early lung branching via an epithelial-mesenchymal interaction

Development ◽  
1995 ◽  
Vol 121 (8) ◽  
pp. 2559-2567 ◽  
Author(s):  
P. Souza ◽  
M. Kuliszewski ◽  
J. Wang ◽  
I. Tseu ◽  
A.K. Tanswell ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Critical Role ◽  
Polymerase Chain Reaction Analysis ◽  
Branching Morphogenesis ◽  
Inhibitory Effect ◽  
Embryonic Lung ◽  
Morphometric Analyses ◽  
Terminal Buds ◽  
Lung Branching

The biological role of platelet-derived growth factor (PDGF)-AA in lung morphogenesis was investigated by incubating embryonic lung explants with phosphorothioate antisense PDGF-A oligonucleotides, which decreased PDGF-AA but not PDGF-BB protein content. Antisense PDGF-A oligonucleotides inhibited DNA synthesis. This inhibitory effect of antisense PDGF-A was reversed by the addition of exogenous PDGF-AA but not PDGF-BB. Morphometric analyses of antisense-treated cultures showed a significant reduction in lung size. The number of terminal buds of the lung explants was significantly decreased by antisense PDGF-A oligonucleotides. PDGF-AA but not PDGF-BB attenuated the inhibitory effect of antisense PDGF-A on early lung branching. Sense PDGF-A had no effect on DNA synthesis and early lung branching. Reverse transcriptase-polymerase chain reaction analysis revealed PDGF-A mRNA expression in the epithelial component of the embryonic lung, while message for PDGF alpha-receptor was expressed in the mesenchyme. Incubation of explants with neutralizing PDGF-AA antibodies also reduced DNA synthesis and early branching morphogenesis. We conclude that PDGF-AA and its receptor represent an important epithelial-mesenchymal interaction which plays a critical role in early lung branching morphogenesis.

Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung

Development ◽  
1997 ◽  
Vol 124 (23) ◽  
pp. 4867-4878 ◽  
Author(s):  
S. Bellusci ◽  
J. Grindley ◽  
H. Emoto ◽  
N. Itoh ◽  
B.L. Hogan
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Lung Development ◽  
Expression Patterns ◽  
Branching Morphogenesis ◽  
Mouse Lung ◽  
Fibroblast Growth ◽  
Embryonic Mouse ◽  
Fibroblast Growth Factor 10

During mouse lung morphogenesis, the distal mesenchyme regulates the growth and branching of adjacent endoderm. We report here that fibroblast growth factor 10 (Fgf10) is expressed dynamically in the mesenchyme adjacent to the distal buds from the earliest stages of lung development. The temporal and spatial pattern of gene expression suggests that Fgf10 plays a role in directional outgrowth and possibly induction of epithelial buds, and that positive and negative regulators of Fgf10 are produced by the endoderm. In transgenic lungs overexpressing Shh in the endoderm, Fgf10 transcription is reduced, suggesting that high levels of SHH downregulate Fgf10. Addition of FGF10 to embryonic day 11.5 lung tissue (endoderm plus mesenchyme) in Matrigel or collagen gel culture elicits a cyst-like expansion of the endoderm after 24 hours. In Matrigel, but not collagen, this is followed by extensive budding after 48–60 hours. This response involves an increase in the rate of endodermal cell proliferation. The activity of FGF1, FGF7 and FGF10 was also tested directly on isolated endoderm in Matrigel culture. Under these conditions, FGF1 elicits immediate endodermal budding, while FGF7 and FGF10 initially induce expansion of the endoderm. However, within 24 hours, samples treated with FGF10 give rise to multiple buds, while FGF7-treated endoderm never progresses to bud formation, at all concentrations of factor tested. Although exogenous FGF1, FGF7 and FGF10 have overlapping activities in vitro, their in vivo expression patterns are quite distinct in relation to early branching events. We conclude that, during early lung development, localized sources of FGF10 in the mesoderm regulate endoderm proliferation and bud outgrowth.

scholarly journals Colorectal Cancer in Inflammatory Bowel Disease

2020 ◽  
Vol 33 (05) ◽  
pp. 305-317
Author(s):  
Martina Nebbia ◽  
Nuha A. Yassin ◽  
Antonino Spinelli
Keyword(s):  
Colorectal Cancer ◽  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Severe Disease ◽  
Critical Role ◽  
Mucosal Inflammation ◽  
Surgical Approaches ◽  
Increased Risk ◽  
Significant Difference ◽  
Inflammatory Bowel

AbstractPatients with inflammatory bowel disease (IBD) are at an increased risk for developing colorectal cancer (CRC). However, the incidence has declined over the past 30 years, which is probably attributed to raise awareness, successful CRC surveillance programs and improved control of mucosal inflammation through chemoprevention. The risk factors for IBD-related CRC include more severe disease (as reflected by the extent of disease and the duration of poorly controlled disease), family history of CRC, pseudo polyps, primary sclerosing cholangitis, and male sex. The molecular pathogenesis of inflammatory epithelium might play a critical role in the development of CRC. IBD-related CRC is characterized by fewer rectal tumors, more synchronous and poorly differentiated tumors compared with sporadic cancers. There is no significant difference in sex distribution, stage at presentation, or survival. Surveillance is vital for the detection and subsequently management of dysplasia. Most guidelines recommend initiation of surveillance colonoscopy at 8 to 10 years after IBD diagnosis, followed by subsequent surveillance of 1 to 2 yearly intervals. Traditionally, surveillance colonoscopies with random colonic biopsies were used. However, recent data suggest that high definition and chromoendoscopy are better methods of surveillance by improving sensitivity to previously “invisible” flat dysplastic lesions. Management of dysplasia, timing of surveillance, chemoprevention, and the surgical approaches are all areas that stimulate various discussions. The aim of this review is to provide an up-to-date focus on CRC in IBD, from laboratory to bedside.

Interaction of epithelium with mesenchyme affects global features of lung architecture: a computer model of development

2007 ◽  
Vol 102 (1) ◽  
pp. 294-305 ◽  
Author(s):  
Seth Tebockhorst ◽  
DongYoub Lee ◽  
Anthony S. Wexler ◽  
Michael J. Oldham
Keyword(s):  
Local Development ◽  
Critical Role ◽  
Branching Morphogenesis ◽  
Global Features ◽  
Local Branching ◽  
Morphogen Gradients ◽  
Simple Rules ◽  
Global Patterns ◽  
Architecture Development

Lung airway morphogenesis is simulated in a simplified diffusing environment that simulates the mesenchyme to explore the role of morphogens in airway architecture development. Simple rules govern local branching morphogenesis. Morphogen gradients are modeled by four pairs of sources and their diffusion through the mesenchyme. Sensitivity to lobar architecture and mesenchymal morphogen are explored. Even if the model accurately represents observed patterns of local development, it could not produce realistic global patterns of lung architecture if interaction with its environment was not taken into account, implying that reciprocal interaction between airway growth and morphogens in the mesenchyme plays a critical role in producing realistic global features of lung architecture.

Mechanical Signaling and Extracellular Matrix in Uterine Fibroids

2017 ◽  
Vol 35 (06) ◽  
pp. 487-493 ◽  
Author(s):  
Saima Rafique ◽  
James Segars ◽  
Phyllis Leppert
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Reproductive Tract ◽  
Critical Role ◽  
Uterine Fibroids ◽  
Female Reproductive Tract ◽  
Benign Tumors ◽  
Mechanical Signaling ◽  
Abnormal Cells ◽  
Fibroid Growth

AbstractFibroids (uterine leiomyomas) are the most common benign tumors of the female reproductive tract. Steroid hormones, growth factors, and cytokines have long been implicated in fibroid growth; however, research suggests that changes in the extracellular matrix and mechanical signaling play a critical role in fibroid growth and differentiation. Studies have shown that growth of fibroids is related to the change in the volume and composition of extracellular matrix with increased deposition of abnormal collagen, glycoproteins, laminins, fibronectins, and an increased osmotic stress. These changes generate mechanical stress which is converted to chemical signals in the cells through mechanotransduction and eventually affects gene expression and protein synthesis. Current studies also suggest that mechanical signaling in fibroid cells is abnormal as evidenced by decreased apoptosis of abnormal cells and deposition of a stiff extracellular matrix promoting fibrosis. Understanding and defining these mechanisms could help design new therapies for the treatment of fibroids.

Key Mechanisms of Early Lung Development

2007 ◽  
Vol 10 (5) ◽  
pp. 335-347 ◽  
Author(s):  
Jun Kimura ◽  
Gail H. Deutsch
Keyword(s):  
Respiratory Tract ◽  
Cell Fate ◽  
Target Genes ◽  
Critical Role ◽  
Hierarchical Classification ◽  
Branching Morphogenesis ◽  
Loss Of Function ◽  
Innovative Strategies ◽  
Downstream Target ◽  
Molecular Events

Lung morphogenesis requires the integration of multiple regulatory factors, which results in a functional air-blood interface required for gas exchange at birth. The respiratory tract is composed of endodermally derived epithelium surrounded by cells of mesodermal origin. Inductive signaling between these 2 tissue compartments plays a critical role in formation and differentiation of the lung, which is mediated by evolutionarily conserved signaling families used reiteratively during lung formation, including the fibroblast growth factor, hedgehog, retinoic acid, bone morphogenetic protein, and Wnt signaling pathways. Cells coordinate their response to these signaling proteins largely through transcription factors, which determine respiratory cell fate and pattern formation via the activation and repression of downstream target genes. Gain- and loss-of-function studies in null mutant and transgenic mice models have greatly facilitated the identification and hierarchical classification of these molecular programs. In this review, we highlight select molecular events that drive key phases of pulmonary development, including specification of a lung cell fate, primary lung bud formation, tracheoesophageal septation, branching morphogenesis, and proximal-distal epithelial patterning. Understanding the genetic pathways that regulate respiratory tract development is essential to provide insight into the pathogenesis of congenital anomalies and to develop innovative strategies to treat inherited and acquired lung disease.

Repair of a Type IV Laryngotracheoesophageal Cleft with Cardiopulmonary Bypass

2002 ◽  
Vol 111 (12) ◽  
pp. 1076-1080 ◽  
Author(s):  
Alain K. Moukheiber ◽  
Alberto Riberi ◽  
Jean Camboulives ◽  
Olivier Paut ◽  
Jean Michel Guys ◽  
...  
Keyword(s):  
Cardiopulmonary Bypass ◽  
Respiratory Distress ◽  
Surgical Repair ◽  
Nissen Fundoplication ◽  
Ventilatory Support ◽  
Single Stage ◽  
Surgical Approaches ◽  
Congenital Defects ◽  
Mechanically Ventilated ◽  
Type Iv

Laryngotracheoesophageal clefts (LTECs) are rare congenital defects of variable severity depending on the extent of malformation. Management of a complete LTEC represents a major surgical and anesthetic challenge. The main problems are achieving adequate operative exposure and maintaining ventilatory support during and after the operation. We describe correction of a type IV LTEC extending down to the carina in an infant who had respiratory distress at birth. Surgical repair was achieved in a single stage by an anterior sternotomy approach on the 11th day of life. The procedure was facilitated by cardiopulmonary bypass. After the operation, the infant was intubated, mechanically ventilated, and sedated. Nissen fundoplication and gastrostomy were carried out on the 11th postoperative day. The child was extubated on the 12th postoperative day. The rationale for this method and its advantages in comparison with other surgical approaches are discussed.

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